Dena Kofahi

Dena Kofahi

6

M. Madadhah

Nour Awamleh & Sara Osama

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Osteomyelitis (OM)

• Osteomyelitis is an infection of bone that leads to tissue destruction, loss of function,

debility and formation of sequestra (dead necrotic bone).

• It’s usually caused by a wide variety of bacteria (including mycobacteria). However, it

can also be caused by fungi and may be associated with viral infections.

➢ What does it mean for viruses to be associated with OM? It means that viruses do

NOT cause osteomyelitis because viruses do NOT cause direct invasion of bone, but

the surrounding inflammation caused by viruses can spread to bone.

• Management is tailored for each individual.

• Tailored management depends on many factors that include:

1) Causative organism

2) Which bone is involved (Different bones have different location, shape, and

structure, so they will also have different infections)

3) State of the vascular supply (if it’s intact or not)

4) State of nerve function

5) Presence of foreign bodies

6) Recent injury

7) The status of the host and if the patient has any associated comorbidities

➢ All of these factors contribute into a wide spectrum of illnesses that fall under the

umbrella of osteomyelitis.

• The spectrum of osteomyelitis can range from extensive (such as tibial or vertebral

osteomyelitis) to localized (such as bone invasion following a tooth abscess) (localized

spectrum could be self-limiting).

• Due to the many factors mentioned above, the syndrome is identified as a spectrum.

The two major classification systems used (mainly to making therapeutic decisions) are:

1) Lee and Waldvogel system: uses three main criteria:

a) Acute or chronic

b) Route of infection: Hematogenous or contiguous (=local)

c) With or without vascular compromise

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2) The Cierny and Mader system: used for long bone osteomyelitis and it takes into

account the location and extent of infection (+other factors).

These tables are very important, read through them carefully. Some extra notes not

mentioned in the tables are:

1- Recall: Bacteria are the microorganisms mostly implicated with osteomyelitis,

followed by fungi, and the least are viruses.

2- S. aureus:

➢ Why is it the MOST likely bacterial pathogen? It is because it has invasive enzymes

that can destroy the local tissue, including collagen and other structural proteins.

➢ It is also the most invasive and aggressive. This could be good for the patient

because this aggressiveness means that the patient will develop symptoms faster

which will lead him/her to seek medical attention.

➢ It can leave metastatic foci in the areas it infects which helps in wider spreading.

➢ Surgery should be considered early to prevent further spread and destruction of

tissue.

3- Coagulase-negative Staphylococci (CoNS): It is characterized with biofilm

formation and can be found on foreign bodies. So, the prosthetic devices in bones

are highly prone to get infected with CoNS (one of the complications of

S. aureus is the most successful in causing osteomyelitis

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surgery). Once biofilm forms, the infection is resistant to treatment and the

prosthetic device must be removed.

4- S. aureus and CoNS are responsible for more than 50% of OM cases. The rest of

the microorganism are responsible for < 50% of cases.

5- Streptococci:

➢ It spreads rapidly through soft tissue →so it’s more likely to spread from soft

tissue into bone (contiguous).

➢ It is highly found in the mouth (normal flora) and is very close to the bone (<5

mm) → so any dental surgery will increase the risk of infection and the

development of bone abscess and osteomyelitis.

6- Enterobacteriaceae: Keep in mind that bones already have low perfusion and with

the development of OM, this perfusion will stop. We give antibiotics for at least a

month to treat OM, and only low, suboptimal doses are reaching the area. So, if

Enterobacteriaceae are found in the infected area → they will develop de novo

resistance (resistance that develops during therapy and didn’t exist before).

7- P. aeruginosa (gram -ve): = biofilm formation + resistance (so it’s very difficult to

treat)

8- Anaerobic bacteria: They are associated with necrosis (devitalized tissue). They

may be synergistic with aerobic bacteria and facultative anaerobes (which help

remove the O2 forming an optimal environment for these anaerobes)

9- Fungi: Candida behaves like bacteria (it replicates fast) and has the additional

benefit of being a eukaryote (it sticks on tissue and has more defenses against our

immune system).

-Note: immunocompromised patients are more likely to get infected with candida

10- M. tuberculosis: It mainly involves vertebral bones. Vertebral OM is more

common in poor countries.

11- Viruses are associated, NOT committed, with OM.

Pathogenesis:

• It is usually due to three main routes:

a) Hematogenous seeding (while in the blood, the bacteria will infect any bone with

problems).

b) Contiguous spread from adjacent infected tissues (it spreads gradually from top

to bottom (the infection from the skin will eventually reach the bone). For

example, an infection may become cellulitis, then fasciitis, then it enters the

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muscle and finally reaches the bone. An example we took is diabetic foot, which

can cause contiguous spread to the bone).

c) Traumatic or surgical inoculation of microorganisms.

• Collection of inflammatory exudates in the bone marrow leads to increased

medullary (bone medulla) pressure →extension of the exudate to bone cortex →

rupture through the periosteum.

• If this periosteal exudate ruptures, the

blood and nerve supply (found in

periosteum) are interrupted → Blockage of

the blood supply leads to necrosis and

separation of dead bone (sequestrum).

• The site of periosteal damage then

becomes site for new bone formation

(involucrum) (as you keep on standing,

your bone tries to adapt by building new

bone, but it can NOT form bone in the area of the sequestrum so it builds the bone

around it forming an involucrum)

• The symptoms are not continuous; the patient might feel pain sometimes, and then

feel nothing. It’s more conspicuous in the beginning but then becomes more

pronounced (like fasciitis).

Classification:

• The Cierny–Mader system is a functional classification, based on the affected portion

of bone and physiological status of the host, and is useful in guiding therapy. It’s only for

long bones. There are four anatomical types:

a) stage 1 = medullary osteomyelitis

(still in the medulla)

b) stage 2 = superficial osteomyelitis

(only superficial or in cortex)

c) stage 3 = localized osteomyelitis

(between stages 1 and 2)

d) stage 4 = diffuse osteomyelitis

(diffused everywhere).

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• There are three physiological

classes:

Etiology:

• Hematogenous osteomyelitis →usually monomicrobial (Why? blood is sterile and has

many defenses so the breach will most likely be by just one microbe. It is very difficult

for the bacteria to be able to enter the blood, survive, and then seed into the tissue).

• Contiguous osteomyelitis →monomicrobial or polymicrobial (Since the

microorganisms are coming from an adjacent infected tissue, it provides an easy

pathway for many microbes to pass, especially when it’s from the skin.)

• In patients with sinuses (occurs when the pressure breaks through to the skin), the

superficial flora may not represent the true pathogen.

•The most common bacterial (>50%) cause of osteomyelitis are Staphylococcus aureus

and CoNS.

• Gram-ve organisms such as Pseudomonas aeruginosa, Escherichia coli, enterococci,

and Propionibacterium may also be found.

• Mycobacterium tuberculosis is a common cause in countries with limited medical

resources (other mycobacterial species that infect bone include M. marinum,

M. chelonei , and M. fortuitum).

• Fungi may include Candida, Coccidioides, Histoplasma, and Aspergillus species.

• The precipitating factors can vary according to route of infection:

1) Prosthetic joint implants and stabilization devices (all foreign objects) are being

used more frequently in orthopedic surgery and are associated with complex

infections.

2) Trauma: if a wound is involved with trauma, that leads to contamination of bone

or surrounding tissue - with significant tissue damage or destruction (For ex. if the

wound is healing, but the patient is diabetic →more likely to have circulating

bacteria (ex. bacteremia) → hematogenous spread)

A = normal host

B = host with local (BL) or systemic (Bs) compromise

C = treatment worse than disease.

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• Not necessary to have an open wound or a compound fracture. In a similar fashion to

what is seen in pyomyositis: damaged tissue and internal bleeding slows down the

circulation which creates favorable conditions for bacterial growth.

• In these damaged tissues, bacteria from peripheral veins or lymphatic channel (low

level bacteremia) may be sufficient to cause infection – in other, normal situations,

circulation would prevent that from occurring.

Bacteremia:

• Bacteremia is a frequent cause of osteomyelitis, and may arise from endocarditis or

from seeding of other infection sites (abscess, boils...etc)

➢ Note: If you see osteomyelitis in someone that does NOT have a wound, then you

need to find the underlying source (ex. endocarditis).

a) Prosthetic joints and S. aureus: Studies show that S. aureus bacteremia causes a

rate of metastatic osteomyelitis approaching 28% if there is a prosthetic joint in

place. It can be complicated by the involvement of methicillin-resistant strains

(MRSA), which are progressively replacing strains that are more susceptible to

antibiotics.

b) Urinary tract circulation: The overlapping circulations of the urinary tract and the

spine is suggested to be the source of vertebral osteomyelitis especially due to

UTI causing pathogens (E. coli and Klebsiella).

➢ Lower lumbar and sacral vertebrae are close to the urinary tract and share the

circulation with it. Vertebral OM is commonly caused by E. coli and Klebsiella

(found in urinary tract). So, UTI → short trip through shared circulation → E. coli

and Klebsiella will reach the vertebrae→ Vertebral OM

c) Limited vascular supply: other predisposing factors →limited arterial and venous

blood supply →limited perfusion to bone to the point of an inadequate response

and poor healing.

d) Diabetes and other host factors contribute significantly to the development of

osteomyelitis through impaired immunity with hyperglycemia, loss of sensation,

vascular disease, and renal failure.

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Epidemiology:

• In the United States, acute osteomyelitis affects ∼0.1–1.8% of the otherwise healthy

adult population.

• After a foot puncture/wound, 30–40% of adults with diabetes develop osteomyelitis.

• MRSA has been steadily replacing MSSA over the last few decades.

• The morbidity and economic burden are greater for MRSA osteomyelitis than that

caused by MSSA. (MSSA itself needs weeks of treatment due to difficulty in reaching the

bone. MRSA adds even more difficulty to the treatment).

• Is MRSA more aggressive because it can evade antimicrobials so has more time to

cause damage? Or is it because their bugs survive longer and get more virulence

factors? Both (note: MRSA doubles the time of therapy)

• Certain countries that have more aging populations and / or populations with more

DM, obesity, and osteoarthritis all contribute to the increase in frequency of

osteomyelitis in these areas.

• Any type of instrumentation through the bone (such as implants, fixation, joint

replacements, and needles in aspiration of bone marrow) may lead to infection in a

small proportion of cases.

• Richer countries have more orthopedic related osteomyelitis, whereas poorer

countries have more TB and brucella or significant wounds in the society (wars,

accidents) →less healthcare services (micro labs, Abx..etc).

Pathogenesis: (can be applied to all pathogens mentioned in this module)

• The most common predisposing factor for osteomyelitis is an area of bone (or

contiguous surrounding tissue) that is defective in viability, blood supply, and sensation

(devitalized area).

• This damaged tissue suffers from reduced oxygenated arterial supply and hindered

venous and lymph out flow (less in, less out = stagnation of blood flow). These are the

prime factors that provide bacteria with optimal growth conditions (O2, nutrients, less

inflammatory cytokines and WBC...etc).

• Host factors such as poor nutrition and immunosuppression may also be relevant.

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• As mentioned, diabetes in adults poses the most significant risk (and further

accentuates the above factors).

• Diabetic neuropathy makes progression of the disease much worse, as the patient

would be unaware of any symptoms (pain sensation reduced) →makes DM a significant

cause for many amputations due to OM.

• In a similar fashion, other causes of immunosuppression will predispose to serious and

frequent infections and OM is no exception.

• Bacterial pathogens that cause OM perpetuate themselves (they maintain their

presence) →they do this by secreting toxins that continually damage surrounding tissue.

• S. aureus is especially strong in this respect, where it colonizes the nasal area in about

one-third of the healthy populace and can produce a variety of cytokines, enzymes, and

toxins that destroy tissue and affect neutrophil response.

➢ OM is NOT a granuloma, but its growth is very similar to the granuloma of TB.

How? There are active bacteria on the sides, and less active bacteria as you go

towards the center. In the center, nutrition and oxygenation are at their lowest

levels → you can find bacteria that are least active and dormant in the center.

(Note: all bacteria have a dormant form. Their dormant form behaves like spores

but is NOT a spore. How? They both have resistance because there is no

metabolic activity (so antibiotics don’t affect them). The difference between them

is that spores have a keratin layer surrounding them).

➢ The first dose of antibiotics will be able to kill the active bacteria but not the

dormant ones. In addition, the blood supply is already compromised so

antimicrobials can hardly reach the bone.

➢ These bacteria will also allow the neutrophils to sequester/ capture them and will

then escape being destroyed inside the neutrophil

➢ In conclusion, there are 2 populations that can perpetuate the bacteria in the

bone: {the bacteria found in the neutrophils + extracellular active population}

→so when extracellular active bacteria decrease in number due to antibiotics,

they will be replenished by the bacteria found inside the neutrophils.

➢ Because of this, osteomyelitis can never be self-limiting.

• Certain strains of S. aureus can survive uptake into the phagocytic vacuoles of

macrophages, this enables them to keep causing tissue damage by consistently evading

host defenses.

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• Basically → two populations of S. aureus, intra- and extracellular, where intracellular

keeps replenishing the extracellular pathogens.

• S. aureus has the capacity to remain dormant (sometimes called NCBV-viable but not

culturable form) → These are resistant forms that hibernate and remain inactive for

decades before infection erupts at sites of old injuries (especially penetrating wounds,

shrapnel…).

• Although CoNS are typically less virulent than S. aureus, but they have been found to

persist by producing biofilm (in which the bacteria communicate together like a

community) that protects them from the host and is thought to be the mechanism that

allows them to persist for many years on, especially, prosthetic joints, with minimal

symptoms.

• In CoNS, it is not uncommon for prosthetic joints to show no symptoms and suddenly

show infection a year or even more later.

• How much other organisms use their biofilm to their advantage is not fully

understood, but biofilm production probably plays an important role in osteomyelitis,

especially in chronic forms.

• Multiple bacteria may be recovered from cultures, especially when there is an entry

wound.

➢ This makes the decision of which one to target in antibiotic therapy difficult.

➢ At this point → Typically common skin flora and colonizing bacteria are not

targeted (if they are, it might make them more aggressive and resistant).

➢ Anaerobic bacteria can often be recovered and can play synergistic role with

other pathogens → these are usually targeted with specific therapy.

➢ Usually a culture of an entry wound is polymicrobial. (For ex., culture results show

the presence E. coli, pseudomonas, S. aureus, and S. epidermidis. Do you think

these staphylococci are truly inside the bone or did they come from the skin

following contamination? It’s difficult to decide).

Clinical features:

•Acute osteomyelitis presentation is usually in pediatric patients and due to

hematogenous spread.

• Whereas subacute to chronic contiguous OM is usually in adults.

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• Onset of pain occurs around the affected site (due to increased pressure on the nerve

in the periosteum → so the surrounding tissue will start hurting. The increasing

pressure will also increase the pain).

• Local and systemic signs of inflammation such as swelling, tenderness, warmth, and

erythema may or may NOT be present (especially in the vertebra, hip or pelvis- NOT IN

LONG BONES).

➢ Note: the deeper the infection, the less likely it is for the inflammatory signs to

be present on the surface.

• Chronic osteomyelitis presentation may begin with local signs of inflammation and/or

presence of a sinus tract (formation of pus that pushes its way until it reaches the skin),

or even pathological fractures (An example may be seen with a man who just stands up,

places pressure on his leg, and suddenly a fracture occurs. Therefore, non-traumatic

fractures suggest weakened bone due to chronic OM).

• Skin ulcers that are prolonged and fail to heal with antibiotic therapy may indicate

underlying osteomyelitis, especially for the case of diabetic foot since OM can

perpetuate the bacteria.

•In such cases, if bone is felt when palpating an ulcer→this can be sufficient to

diagnose osteomyelitis

Diagnosis:

• Usually based on clinical suspicion, and then confirmed by radiology. Microbiology

and pathology methods can then be used.

➢ We confirm the diagnosis by radiology. Then, we use microbiological testing to

identify the pathogen and what drug(s) to use. Microbiology is not used for

diagnosis because you don’t retrieve the bone specimen unless you’re sure it’s

osteomyelitis and the specimen was taken for deciding suitable treatment.

❖ Blood tests

➢ White cell count may be raised but can be normal.

➢ Inflammatory markers (ESR and CRP) are usually high (their high levels don’t

confirm it’s osteomyelitis but suggest a suspicion of it so they might help in the

diagnosis).

➢ CRP changes occur earlier in bacterial infection.

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➢ However, ESR and CRP are not specific and can be elevated in conditions other

than osteomyelitis

• Blood cultures are more likely positive in vertebral infection and in hematogenous

spread (clavicle, pubis), rather than long bones.

❖ Radiology

• Plain X-ray may show changes after 1-2 weeks.

• May eliminate the need for further imaging studies.

• Bone loss, sequestra, periosteal elevation or swelling (which can develop early on),

and shadows around foreign bodies are hallmarks of bone infection.

• CT or MRI scans are the investigations of choice (MRI is both specific and sensitive).

• MRI may be contraindicated in patients with metal ware; which may also cause

artifacts on the CT scan.

→The following x-ray shows fracture and an abscess being

formed.

➔ X-ray (A) shows elevation of periosteum

and an involucrum forming.

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❖ Biopsy

• An open or percutaneous bone biopsy should be taken and sent to microbiology and

histology labs.

• Needle aspiration of pus collection is both Rx and Dx for the pathogen.

➢ Because when you aspirate the fluid of the abscess, you aspirate everything.

Therefore, needle aspiration is both therapeutic and diagnostic.

• Biopsy can be taken in open surgery with debridement of all necrotic tissue, which is

again both Rx and Dx, as it revitalizes the tissue.

• Antibiotics should be stopped 48-72 hours prior to biopsy to improve the yield of the

culture.

➢ Antibiotics are stopped 2 days before because you want an accurate reading of

the sensitivity profile of the bacteria and to make sure that the bacteria causing

OM is still there. The treatment is long and lasts from 4 to 6 weeks, so you want

to make sure it is the most appropriate treatment for the case.

• Swabs from sinus tracts are of questionable value and may often just be presenting

the local flora.

• PCR and sequencing technologies are becoming more standard in diagnosis to detect

and identify specific organisms

➢ PCR shows the microorganisms’ sensitivity to Abx (antibiotics) within hours

instead of days or weeks.

➢ You can determine the sensitivity of the bacteria by using PCR since you can find

the gene that is responsible for the resistance. For example, you can look for the

mecA gene seen in MRSA.

➢ Within the next 5-10 years, a new technology (amino acid sequencer) may be

replacing PCR.

Management:

• General principles:

➢ The aim of treatment is to eradicate the causative agent and restore (or at least

preserve) the function of the bone.

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➢ OM in adults is usually treated with a combination of surgical debridement and

antibiotic therapy.

• Surgery: the principles of surgical therapy are debridement of infected tissue, removal

of metal ware, management of dead space (using a flap), wound closure, and

stabilization of infected fractures.

Antimicrobial therapy:

The spectrum of osteomyelitis treatment is very wide:

• Choice of Abx therapy is based on culture and sensitivity results. However, the

duration is unknown and most experts treat for 4-6 weeks IV therapy (the treatment is

prolonged because it is hard to reach the bone).

• The addition of rifampicin to β-lactams was shown to be effective in certain

staphylococcal OM animal models and is often used in infections, particularly those

involving prosthetic material.

• Patients are usually discharged once they are clinically stable (after debridement and

any other actions needed to reach a point where the patient is stable) and treated as an

outpatient with an IV antimicrobial catheter.

➢ There is a role for oral treatment, but IV treatment is superior to oral treatment,

especially to increase the dose of the drug reaching the defective bone.

• Hyperbaric oxygen has been shown to be effective in animal studies (no data in

humans) and can be used as adjunctive therapy.

• Negative pressure wound therapy (vacuum-assisted closure) is being increasingly used

and may accelerate wound healing in complex wounds and in diabetic patients.

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Some notes to know about the following table:

1- Ceftriaxone (every 24 hours) is better than Oxacillin (every 6 hours) since it will

improve patient compliance. However, it may be overkill. Oxacillin may be more

active than cephalosporins as well.

2- MRSA patients should take vancomycin or other forms.

3- For streptococci, penicillin works just fine.

4- Enterococci (gram positive streptococci) are very resistant because they live with

enteric bacteria, so when we give them regular systemic anti-staph and strep

medication, it will not work. Therefore, we have to supplement it with the drug

combination mentioned in the table: vancomycin and sometimes

aminoglycosides.

➢ Gentamicin: It targets proteins. Gram negative bacteria are more susceptible to it

than gram positive bacteria (although gentamicin works on both). It is also

bactericidal and when combined with penicillin it will have a synergistic effect.

5- Enterobacteriaceae: Ciprofloxacin is an excellent tissue penetrator, even at the

bone. So, if there is a susceptibility for Ciprofloxacin, it is a good medication to

use.

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• There is still controversy about the optimal route and duration of therapy.

• However, a 4 to 6 week course of IV therapy remains the standard and is the usual

recommended minimum.

• Although in pediatric populations, some studies are suggesting adequate treatment

with somewhat shorter duration + oral therapy.

• Because some of the active agents reach comparable levels when given by mouth, a

switch from the recommended IV administration to oral therapy may be appropriate in

some situations.

• Duration is increased for more extensive disease or with patients with additional

comorbidity (see previous classification-Cierny Mader) + vertebral OM (no comorbidity

and local disease would require less).

Complications:

• Sinus tract formation.

• Pathological fractures→ because the sequestra make that specific area of bone less

able to bear weight and is prone to fracture.

• Hematogenous spread and sepsis, especially in aggressive disease.

• Tumors in patients with long-standing (4–5 years).

➢ In rare instances, chronic inflammation and infection may lead to malignant

transformation into squamous cell carcinoma or sarcoma.

➢ Osteomyelitis, e.g. squamous cell carcinoma (commonest), fibrosarcoma,

myeloma, lymphoma, plasmacytoma, angiosarcoma, rhabdomyosarcoma, and

malignant fibrous histiocytoma.

Prognosis:

• Varies based on all the factors that are included in the classification systems.

• Vertebral, immunocompromised and late Dx → poorer prognosis

• Mandible following tooth extraction, early proper treatment → better prognosis.

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Prevention:

• Osteomyelitis can be prevented with better preoperative infection and prevention

measures.

• Agents such as mupirocin and chlorhexidine (as topical agents on the skin) have been

shown to be successful in preventing operative infections (which are a common cause in

prosthetic joins OM).

• Early Dx and treatment of other infection routes (abscess, bacteremia, boil…etc).

• Early surgical treatment of wounds (especially extensive ones) have better outcome.

• Sacral ulcers can often be a point of infection in bed ridden patients → and easily

overlooked.

Good Luck